Role of RUNX2 in Breast Carcinogenesis

Abstract

RUNX2 is a transcription factor playing the major role in osteogenesis, but it can be involved in DNA damage response, which is crucial for cancer transformation. RUNX2 can interact with cell cycle regulators: cyclin-dependent kinases, pRB and p21Cip1 proteins, as well as the master regulator of the cell cycle, the p53 tumor suppressor. RUNX2 is involved in many signaling pathways, including those important for estrogen signaling, which, in turn, are significant for breast carcinogenesis. RUNX2 can promote breast cancer development through Wnt and Tgfβ signaling pathways, especially in estrogen receptor (ER)-negative cases. ERα interacts directly with RUNX2 and regulates its activity. Moreover, the ERa gene has a RUNX2 binding site within its promoter. RUNX2 stimulates the expression of aromatase, an estrogen producing enzyme, increasing the level of estrogens, which in turn stimulate cell proliferation and replication errors, which can be turned into carcinogenic mutations. Exploring the role of RUNX2 in the pathogenesis of breast cancer can lead to revealing new therapeutic targets.

Keywords: DNA damage response; RUNX2; breast cancer; cell cycle; estrogen.

Figure 1

The structure of the RUNX2 protein (top) and gene (bottom). HDAC6, TLE, Pim-1, ERK, Cdks, MEK1, pRB, p53 and ER denote proteins interacting with RUNX2. VDR/RXR, NF-1, AP-1, parathyroid hormone (PTH), estrogen receptor (ER) and TCF/LEF (T-cell factor/lymphoid enhancer factor) are factors interacting with the RUNX2 gene promoter. NLS: nuclear localization signal peptide; RUNT: the runt domain; P1 and P2: alternative promoters, numbers in boxes denote exons; QA: polyglutamate and alanine motif; TA/ID: transactivation/inhibitory domain; VWRPY: C-terminal repression motif; VDR/RXR: vitamin D receptor/retinoic acid X receptor.

Figure 2

Signaling cascade following DNA damage and important role of RUNX2. The first step is DNA damage sensing through sensor proteins (yellow) to a downstream signaling effectors (orange) to effectors coordinating DNA damage response and determining cell fate (green).

Figure 3

RUNX2 and estrogen signaling pathways in the control of cellular apoptosis and differentiation. Sharp arrows indicate positive, while blunt arrows—negative regulation. FasL: fas ligand; GPR30: G protein-coupled estrogen receptor; BMP-4: bone morphogenetic protein 4.

Figure 4

Important role of RUNX2 in estrogen-dependent breast cancer development and progression. Blue arrows indicate positive influence, while red are negative. Snai2: breast cancer-related transcription factor; MMPs: matrix metalloproteinase; VEGF: vascular endothelial growth factor.